Converging evidence from our lab and others suggests that an independent correlation exists between cerebral hemodynamic failure and cognitive impairment in patients with high-grade carotid artery stenosis. The implication of such a relationship is that cognitive dysfunction due to hemodynamic failure appears to represent one of the few examples of treatable cognitive impairment, yet current management algorithms for carotid disease focus only on the prevention of recurrent stroke. In addition, improved medical therapy for patients with carotid artery stenosis such as the widespread use of statins and better blood pressure control has led a clinical practice trend toward medical management for patients with asymptomatic ICA stenosis. The demonstration that some patients with carotid artery stenosis are living with reversible cognitive impairment would have compelling public-health impact, however, with 124,000 individuals over age 60 currently harboring high-grade carotid stenosis in the US alone. It has only been over the last few years -- as the tools to measure cerebral hemodynamic function have become increasingly sophisticated and the cognitive profile of patients with vascular cognitive impairment (VCI) has become clearer -- that we are presented with the opportunity to advance our understanding of the physiological link between hemodynamic failure and cognitive dysfunction. Such proof of concept (followed by a clinical trial) is necessary for any shift in clinical practice to be considered. We plan to study 158 patients over a 5-year period to determine the spectrum of cognitive dysfunction in those with e80%, both at baseline and over a 2-year follow up period. We will investigate the correlation of cognitive dysfunction with 4 hemodynamic factors: cerebral blood flow (CBF) as measured quantitatively with arterial spin labeling (ASL) MRI, cerebral vasomotor reactivity (VMR) and dynamic cerebral autoregulation (DCA) as measured by transcranial Doppler, and neurovascular coupling measured quantitatively with functional ASL imaging of the hemodynamic response to task-related neuronal activity. CBF and all 3 types of blood flow regulation have been reported to be impaired in the setting of carotid artery disease, and all have been associated with neurological dysfunction. It is as yet unknown, however, whether these hemodynamic variables mediate cognitive impairment in the setting of carotid artery disease. Successful elucidation of these hemodynamic mechanisms will contribute substantially to our knowledge of vascular cognitive impairment (VCI), and potentially lead to a significant shift in treatment algorithms for carotid artery stenosis. PUBLIC HEALTH RELEVANCE: Cognitive impairment is of increasing interest in our aging population. Causes are incompletely understood. It is hypothesized that low blood flow to the brain due to carotid artery disease contributes to cognitive impairment. Demonstrating the link between cerebral blood flow dysregulation and cognitive impairment could lead to a major shift in the treatment algorithms of carotid artery disease affecting tens of thousands of individuals in the US each year.